2-benzylaminodihydropteridinones, process for their manufacture and use thereof as medicaments

ABSTRACT

The present invention relates to new 2-benzylaminodihydropteridinones of general formula (I) 
                         
wherein the groups R 1  to R 7 , R 10  and R 11  have the meanings given in the claims and specification, the isomers thereof, methods of preparing these dihydropteridinones and their use as medicaments.

CROSS-REFERENCE TO RELATED APPLICATIONS

This is a continuation application and claims the benefit of U.S. patentapplication Ser. No. 11/157,883 filed Jun. 21, 2005, the entirety ofwhich is incorporated herein by reference.

The present invention relates to new 2-benzylaminodihydropteridinones ofgeneral formula (I)

wherein the groups R¹ to R⁷, R¹⁰ and R¹¹ have the meanings given in theclaims and specification, the isomers thereof, processes for preparingthese dihydropteridinones and their use as medicaments.

BACKGROUND TO THE INVENTION

Pteridinone derivatives are known from the prior art as activesubstances with an antiproliferative activity. WO 01/019825 and WO03/020722 describe the use of pteridinone derivatives for the treatmentof tumoral diseases.

Tumour cells wholly or partly elude regulation and control by the bodyand are characterised by uncontrolled growth. This is based on the onehand on the loss of control proteins, such as e.g. Rb, p16, p21 and p53and also on the activation of so-called accelerators of the cell cycle,the cyclin-dependent kinases (CDK's).

In addition, the protein kinase Aurora B has been described as having anessential function during entry into mitosis. Aurora B phosphorylateshistone H3 at Ser10 and thus initiates chromosome condensation (Hsu etal. 2000, Cell 102:279-91). A specific cell cycle arrest in the G2/Mphase may however also be triggered e.g. by the inhibition of specificphosphatases such as e.g. Cdc25C (Russell and Nurse 1986, Cell45:145-53). Yeasts with a defective Cdc25 gene arrest in the G2 phase,while overexpression of Cdc25 leads to premature entry into the mitosisphase (Russell and Nurse 1987, Cell 49:559-67). Moreover, an arrest inthe G2/M phase may also be triggered by the inhibition of certain motorproteins, the so-called kinesins such as e.g. Eg5 (Mayer et al. 1999,Science 286:971-4), or by agents which stabilise or destabilisemicrotubules (e.g. colchicin, taxol, etoposide, vinblastin, vincristine)(Schiff and Horwitz 1980, Proc Nat Acad Sci USA 77:1561-5).

In addition to the cyclin-dependent and Aurora kinases the so-calledpolo-like kinases, a small family of serine/threonine kinases, play animportant part in the regulation of the eukaryotic cell cycle. Hitherto,the polo-like kinases PLK-1, PLK-2, PLK-3 and PLK-4 have been describedin the literature. PLK-1 in particular has been shown to play a centralpart in the regulation of the mitosis phase. PLK-1 is responsible forthe maturation of the centrosomes, for the activation of phosphataseCdc25C, and for the activation of the Anaphase Promoting Complex (Gloveret al. 1998, Genes Dev. 12:3777-87; Qian et al. 2001, Mol Biol Cell.12:1791-9). The injection of PLK-1 antibodies leads to a G2 arrest inuntransformed cells, whereas tumour cells arrest in the mitosis phase(Lane and Nigg 1996, J Cell Biol. 135:1701-13). Overexpression of PLK-1has been demonstrated for various types of tumour, such asnon-small-cell lung cancer, plate epithelial carcinoma, breast andcolorectal carcinoma (Wolf et al. 1997, Oncogene 14:543-549; Knecht etal. 1999, Cancer Res. 59:2794-2797; Wolf et al. 2000, Pathol. Res.Pract. 196:753-759; Takahashi et al. 2003, Cancer Sci. 94:148-52).Therefore, this category of proteins also constitutes an interestingapproach to therapeutic intervention in proliferative diseases (Liu andErikson 2003, Proc Nat Acad Sci USA 100:5789-5794).

The resistance of many types of tumours calls for the development of newpharmaceutical compositions for combating tumours.

The aim of the present invention is to provide new compounds having anantiproliferative activity.

DETAILED DESCRIPTION OF THE INVENTION

Surprisingly it has been found that compounds of general formula (I)wherein the groups R¹ to R⁷, R¹⁰ and R¹¹ have the meanings givenhereinafter act as inhibitors of specific cell cycle kinasesparticularly the polo-like kinases. The compounds named have anantiproliferative activity, in that they arrest cells in the mitosisphase of the cell cycle before programmed cell death is initiated in thearrested cells. Thus, the compounds according to the invention may beused for example to treat diseases connected with the activity ofspecific cell cycle kinases and characterised by excessive or abnormalcell proliferation.

The present invention therefore relates to compounds of general formula(I)

whereinR¹, R² which may be identical or different, denote a group selected fromamong optionally substituted C₁-C₁₀-alkyl, C₂-C₁₀-alkenyl,C₂-C₁₀-alkynyl, aryl, heteroaryl, C₃-C₈-cycloalkyl,C₃-C₈-heterocycloalkyl, —X-aryl, —X-heteroaryl, —X-cycloalkyl,—X-heterocycloalkyl, —NR⁸-aryl, —NR⁸-heteroaryl, —NR⁸-cycloalkyl, and—NR⁸-heterocycloalkyl,ora group selected from among hydrogen, halogen, COXR⁸, CON(R⁸)₂, COR⁸ andXR⁸,orR¹ and R² together denote a 2- to 5-membered alkyl bridge which maycontain 1 to 2 heteroatoms,R³ denotes hydrogen or a group selected from among optionallysubstituted C₁-C₁₂-alkyl, C₂-C₁₂-alkenyl, C₂-C₁₂-alkynyl, aryl,heteroaryl, C₃-C₁₂-cycloalkyl, C₃-C₁₂-cycloalkenyl,C₇-C₁₂-polycycloalkyl, C₇-C₁₂-polycycloalkenyl andC₅-C₁₂-spirocycloalkyl orR¹ and R³ or R² and R³ together denote a saturated or unsaturatedC₃-C₄-alkyl bridge which may contain 1 to 2 heteroatoms,R⁴ denotes optionally substituted aryl or heteroaryl,R⁵ denotes a group selected from among hydrogen, CHO, XH, —X—C₁-C₂-alkyland an optionally substituted C₁-C₃-alkyl group,R⁶ denotes a group selected from among hydrogen, NH₂, XH, halogen and aC₁-C₃-alkyl group optionally substituted by one or more halogen atoms,R⁷ denotes hydrogen or —CO—C₁-C₄-alkyl, —CO—NH—C₁-C₄-alkyl,—CO—X—C₁-C₄-alkyl, andX in each case independently of one another denote O or S,R⁸ in each case independently of one another denote hydrogen or a groupselected from among optionally substituted C₁-C₄-alkyl, C₂-C₄-alkenyl,C₂-C₄-alkynyl, benzyl and phenyl,R¹⁰ and R¹¹ in each case independently of one another denote hydrogen ora group selected from among optionally substituted C₁-C₄-alkyl,or R¹⁰ and R¹¹ together denote a 2-5 membered alkyl bridge,optionally in the form of the tautomers, racemates, enantiomers,diastereomers and mixtures thereof, and optionally the pharmacologicallyacceptable acid addition salts, solvates or hydrates thereof.

Preferred are compounds of formula (I), wherein

R¹ to R⁴ have the meanings specified,

R⁵ denotes methyl, and

R⁶ and R⁷ denote hydrogen,

R¹⁰ and R¹¹ in each case independently of one another denote hydrogen ormethyl,

or

R¹⁰ and R¹¹ together denote cyclopropyl.

#

Also preferred are compounds of formula (I), wherein

R³ to R⁷, R¹⁰ and R¹¹ have the meanings given above and

R¹, R² which may be identical or different denote hydrogen or a groupselected from among optionally substituted C₁-C₆-alkyl, C₂-C₆-alkenyl,and C₂-C₆-alkynyl,

or

R¹ and R² together denote a 2- to 5-membered alkyl bridge.

Particularly preferred are compounds of formula (I), wherein

R¹, R³, R⁴ to R⁷, R¹⁰ and R¹¹ have the meanings given above,

and

R³ is hydrogen or contains a group, selected from among optionallysubstituted C₁-C₁₂-alkyl, C₂-C₁₂-alkenyl, C₂-C₁₂-alkynyl andC₆-C₁₄-aryl, or

a group selected from among optionally substituted and/or bridgedC₃-C₁₂-cycloalkyl, C₃-C₁₂-cycloalkenyl, C₇-C₁₂-polycycloalkyl,C₇-C₁₂-polycycloalkenyl and C₅-C₁₂-spirocycloalkyl.

Also particularly preferred are compounds of formula (I), wherein

R¹ to R³, R⁵ to R⁷, R¹⁰ and R¹¹ have the meanings given above,

and

R⁴ denotes a group of general formula

R⁹ which may be identical or different, denotes a group selected fromamong optionally substituted C₁-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl,—O—C₁-C₆-alkyl, —O—C₂-C₆-alkenyl, —O—C₂-C₆-alkynyl,C₃-C₆-heterocycloalkyl, C₃-C₆-cycloalkyl, aryl, heteroaryl, —O-aryl,—O-heteroaryl, —O-cycloalkyl, and —O-heterocycloalkyl or a groupselected from among hydrogen, —CONH₂, —COOR⁸—OCON(R⁸)₂, —N(R⁸)₂,—NHCOR⁸—NHCON(R⁸)₂, —NO₂, CF₃, halogen, —O—C₁-C₆-alkyl-Q¹,—CONR⁸—C₁-C₁₀-alkyl-Q¹, —CONR⁸—C₂-C₁₀-alkenyl-Q¹, —CONR⁸-Q², halogen,OH, —SO₂R⁸, —SO₂N(R⁸)₂, —COR⁸—COOR⁸, —N(R⁸)₂, —NHCOR⁸,—CONR⁸OC₁-C₁₋₁₀-alkyl-Q¹ and CONR⁸O-Q²,R⁸ in each case independently of one another denotes hydrogen or a groupselected from among optionally substituted C₁-C₄-alkyl, C₂-C₄-alkenyl,C₂-C₄-alkynyl and phenyl,Q¹ denotes hydrogen, —NHCOR⁸, or a group selected from among anoptionally substituted —NH-aryl, —NH-heteroaryl, aryl, heteroaryl,C₃-C₈-cycloalkyl and heterocycloalkyl group,Q² denotes hydrogen or a group selected from among an optionallysubstituted aryl, heteroaryl and C₃-C₈-cycloalkyl group,andn denotes 0, 1, 2, 3, 4 or 5.

Particularly preferred are compounds of formula (I), wherein

Q¹, Q², n, R⁴ to R⁹ have the meanings given above,

R¹, R² which may be identical or different, denote hydrogen or a groupselected from among methyl, ethyl, propyl, allyl and propargyl

or

R¹ and R² together denote cyclopropyl,

R³ denotes hydrogen, or optionally substituted C₁-C₆-alkyl or optionallysubstituted and/or bridged C₃-C₁₂-cycloalkyl, and

R¹⁰ and R¹¹ represent hydrogen.

Most preferred are compounds of formula (I), wherein

Q¹, Q², n, R¹ to R⁴, R⁶ to R⁸, R¹⁰ and R¹¹ have the meanings givenabove, and

R⁹ which may be identical or different, denote hydrogen or a groupselected from among halogen, (C₁-C₆-alkyl)₂N, CF₃, NH₂SO₂,—CONH—C₆-C₁₄-aryl, —CONH—C₁-C₄-alkyl-C₆-C₁₄-aryl and —O—C₁-C₄-alkyl.

The invention further relates to compounds of formula (I) for use aspharmaceutical compositions.

Of particular importance according to the invention are compounds offormula (I) for use as pharmaceutical compositions with anantiproliferative activity.

The invention also relates to the use of a compound of formula (I) forpreparing a pharmaceutical composition for the treatment and/orprevention of diseases selected from among cancer, bacterial and viralinfections, inflammatory and autoimmune diseases, chemotherapy-inducedalopecia and mucositis, cardiovascular diseases, nephrological diseases,as well as chronic and acute neurodegenerative diseases, preferably forthe treatment of cancer, inflammatory and autoimmune diseases,particularly preferably for the treatment of cancer and inflammatorydiseases.

The invention further relates to the use of a compound of formula (I)for preparing a pharmaceutical composition for inhibiting the polo-likekinases, particularly the polo-like kinase PLK-1.

The invention further relates to the use of a compound of formula (I)for preparing a pharmaceutical composition for the treatment and/orprevention of tumour diseases based on the overexpression of thepolo-like kinases, particularly the PLK-1 kinases.

The invention further relates to a method for the treatment and/orprevention of diseases selected from among cancer, bacterial and viralinfections, inflammatory and autoimmune diseases, chemotherapy-inducedalopecia and mucositis, cardiovascular diseases, nephrological diseases,as well as chronic and acute neurodegenerative diseases, preferably forthe treatment of cancer, inflammatory and autoimmune diseases,particularly preferably for the treatment of cancer and inflammatorydiseases, in which an effective amount of a compound of formula (I) isadministered to a patient.

The invention also relates to pharmaceutical preparations, containing asactive substance one or more compounds of general formula (I) optionallycombined with conventional excipients and/or carriers.

The term alkyl groups, including alkyl groups which are a part of othergroups, denotes branched and unbranched alkyl groups with 1 to 12 carbonatoms, preferably 1-6, most preferably 1-4 carbon atoms, such as, forexample: methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl,nonyl and decyl. Unless otherwise stated, the abovementioned termspropyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl and decyl include allthe possible isomeric forms. For example, the term propyl includes thetwo isomeric groups n-propyl and iso-propyl, the term butyl includesn-butyl, iso-butyl, sec. butyl and tert.-butyl, the term pentyl includesiso-pentyl, neopentyl, etc.

In the abovementioned alkyl groups one or more hydrogen atoms mayoptionally be replaced by other groups. For example these alkyl groupsmay be substituted by methyl, chlorine or fluorine, preferably fluorine.All the hydrogen atoms of the alkyl group may optionally also bereplaced.

The term alkyl bridge, unless otherwise stated, denotes branched andunbranched alkyl groups with 2 to 5 carbon atoms, for example ethylene,propylene, isopropylene, n-butylene, iso-butyl, sec. butyl andtert.-butyl etc. bridges. Ethylene, propylene and butylene bridges areparticularly preferred. In the alkyl bridges mentioned 1 to 2 C-atomsmay optionally be replaced by one or more heteroatoms selected fromamong oxygen, nitrogen or sulphur.

The term alkenyl groups (including those which are a part of othergroups) denotes branched and unbranched alkylene groups with 2 to 10carbon atoms, preferably 2-6 carbon atoms, most preferably 2-3 carbonatoms, provided that they have at least one double bond. Examplesinclude: ethenyl, propenyl, butenyl, pentenyl etc. Unless otherwisestated, the abovementioned terms propenyl, butenyl, etc also include allthe possible isomeric forms. For example, the term butenyl includes1-butenyl, 2-butenyl, 1-methyl-1-propenyl, 1-methyl-2-propenyl,2-methyl-1-propenyl, 2-methyl-2-propenyl and 1-ethyl-1-ethenyl.

In the abovementioned alkenyl groups, unless otherwise stated, one ormore hydrogen atoms may optionally be replaced by other groups. Forexample, these alkenyl groups may be substituted by methyl, chlorine orfluorine, preferably fluorine. All the hydrogen atoms of the alkenylgroup may optionally also be replaced.

The term alkynyl groups (including those which are a part of othergroups) denotes branched and unbranched alkynyl groups with 2 to 10carbon atoms, provided that they have at least one triple bond, forexample ethynyl, propargyl, butynyl, pentynyl, hexynyl etc., preferablyethynyl or propynyl.

In the abovementioned alkynyl groups, unless otherwise stated, one ormore hydrogen atoms may optionally be replaced by other groups. Forexample, these alkynyl groups may be substituted by methyl, chlorine orfluorine, preferably fluorine. All the hydrogen atoms of the alkynylgroup may optionally also be replaced.

The term aryl denotes an aromatic ring system with 6 to 14 carbon atoms,preferably 6 or 10 carbon atoms, preferably phenyl, which, unlessotherwise stated, may carry one or more of the following substituents,for example: OH, NO₂, CN, OMe, —OCHF₂, —OCF₃, —NH₂, halogen, preferablyfluorine or chlorine, C₁-C₁₀-alkyl, preferably C₁-C₅-alkyl, preferablyC₁-C₃-alkyl, particularly preferably methyl or ethyl, —O—C₁-C₃-alkyl,preferably —O-methyl or —O-ethyl, —COOH, —COO—C₁-C₄-alkyl, preferably—O-methyl or —O-ethyl, or —CONH₂.

Examples of heteroaryl groups wherein up to two C atoms are replaced byone or two nitrogen atoms are, for example, pyrrole, pyrazole,imidazole, triazole, pyridine, pyrimidine, while each of theabove-mentioned heteroaryl rings may optionally also be anellated to abenzene ring, preferably benzimidazole, and these heterocycles, unlessstated to the contrary, may for example carry one or more of thefollowing substituents: F, Cl, Br, OH, OMe, methyl, ethyl, CN, CONH₂,NH₂, optionally substituted phenyl, optionally substituted heteroaryl,preferably optionally substituted pyridyl.

Examples of cycloalkyl groups are cycloalkyl groups with 3-12 carbonatoms, for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl or cyclooctyl, preferably cyclopropyl, cyclopentyl orcyclohexyl, while each of the above-mentioned cycloalkyl groups mayoptionally also carry one or more substituents, for example: OH, NO₂,CN, OMe, —OCHF₂, —OCF₃, —NH₂ or halogen, preferably fluorine orchlorine, C₁-C₁₀-alkyl, preferably C₁-C₅-alkyl, preferably C₁-C₃-alkyl,particularly preferably methyl or ethyl, —O—C₁-C₃-alkyl, preferably—O-methyl or —O-ethyl, —COOH, —COO—C₁-C₄-alkyl, preferably —COO-methylor —COO-ethyl or —CONH₂. Particularly preferred substituents of thecycloalkyl groups are ═O, OH, NH₂, methyl or F.

Examples of cycloalkenyl groups are cycloalkyl groups with 3-12 carbonatoms which have at least one double bond, for example cyclopropenyl,cyclobutenyl, cyclopentenyl, cyclohexenyl or cycloheptenyl, preferablycyclopropenyl, cyclopententyl or cyclohexenyl, while each of theabove-mentioned cycloalkenyl groups may optionally also carry one ormore substituents.

“═O” denotes an oxygen atom linked by a double bond.

Examples of heterocycloalkyl groups, unless otherwise stated in thedefinitions, are 3 to 12 membered, preferably 5-, 6- or 7-membered,saturated or unsaturated heterocycles, which may contain as heteroatomsnitrogen, oxygen or sulphur, for example tetrahydrofuran,tetrahydrofuranone, γ-butyrolactone, α-pyran, γ-pyran, dioxolane,tetrahydropyran, dioxane, dihydrothiophene, thiolane, dithiolane,pyrroline, pyrrolidine, pyrazoline, pyrazolidine, imidazoline,imidazolidine, tetrazole, piperidine, pyridazine, pyrimidine, pyrazine,piperazine, triazine, tetrazine, morpholine, thiomorpholine, diazepan,oxazine, tetrahydro-oxazinyl, isothiazole, pyrazolidine, preferablymorpholine, pyrrolidine, piperidine or piperazine, while theheterocyclic group may optionally carry substituents, for exampleC₁-C₄-alkyl, preferably methyl, ethyl or propyl.

Examples of polycycloalkyl groups are optionally substituted, bi-, tri-,tetra- or pentacyclic cycloalkyl groups, for example pinane,2,2,2-octane, 2,2,1-heptane or adamantane. Examples of polycycloalkenylgroups are optionally bridged and/or substituted, 8-membered bi-, tri-,tetra- or pentacyclic cycloalkenyl groups, preferably bicycloalkenyl ortricycloalkenyl groups, if they contain at least one double bond, forexample norbornene.

Examples of spiroalkyl groups are optionally substituted spirocyclicC₅-C₁₂ alkyl groups.

The term halogen generally denotes fluorine, chlorine, bromine oriodine, preferably fluorine, chlorine or bromine, particularlypreferably chlorine.

The compounds according to the invention may be present in the form ofthe individual optical isomers, mixtures of the individual enantiomers,diastereomers or racemates, in the form of the tautomers, in the form ofthe solvates, preferably in the form of the hydrates thereof and also inthe form of the free bases or the corresponding acid addition salts withpharmacologically acceptable acids—such as for example acid additionsalts with hydrohalic acids, for example hydrochloric or hydrobromicacid, or organic acids, such as for example oxalic, fumaric, diglycolicor methanesulphonic acid.

The substituent R¹ may be a group selected from among optionallysubstituted C₁-C₁₀-alkyl, preferably C₁-C₄-alkyl, particularlypreferably methyl, ethyl or propyl, C₂-C₁₀-alkenyl, preferably allyl,C₂-C₁₀-alkynyl, preferably propargyl, aryl, heteroaryl,C₃-C₈-cycloalkyl, C₃-C₈-heterocycloalkyl, —X-aryl, —X-heteroaryl,—X-cycloalkyl, —X-heterocycloalkyl, —NR⁸-aryl, —NR⁸-heteroaryl,—NR⁸-cycloalkyl, and —NR⁸-heterocycloalkyl,

or a group selected from among hydrogen, halogen, COXR⁸, CON(R⁸)₂, COR⁸and XR⁸, preferably hydrogen.

Preferably the substituent R¹ denotes ethyl or hydrogen, particularlypreferably hydrogen.

The substituent R² may represent a group selected from among optionallysubstituted C₁-C₁₀-alkyl, preferably C₁-C₄-alkyl, particularlypreferably methyl, ethyl or propyl, C₂-C₁₀-alkenyl, preferably allyl,C₂-C₁₀-alkynyl, preferably propargyl, aryl, heteroaryl,C₃-C₈-cycloalkyl, C₃-C₈-heterocycloalkyl, —X-aryl, —X-heteroaryl,—X-cycloalkyl, —X-heterocycloalkyl, —NR⁸-aryl, —NR⁸-heteroaryl,—NR⁸-cycloalkyl, and —NR⁸-heterocycloalkyl,

or a group selected from among hydrogen, halogen, COXR⁸, CON(R⁸)₂, COR⁸and XR⁸, preferably hydrogen.

Preferably the substituent R² denotes ethyl or hydrogen, particularlypreferably ethyl.

The substituents R¹ and R² may together denote a 2- to 5-membered alkylbridge, preferably a 2-membered alkyl bridge which may contain 1 to 2heteroatoms, for example oxygen, sulphur or nitrogen, preferably oxygenor nitrogen.

The substituent R³ may denote hydrogen or a group selected from amongoptionally substituted C₁-C₁₂-alkyl, preferably C₁-C₆-alkyl,C₂-C₁₂-alkenyl, C₂-C₁₂-alkynyl, aryl, heteroaryl, —C₃-C₁₂-cycloalkyl,C₃-C₁₂-cycloalkenyl, C₇-C₁₂-polycycloalkyl, C₇-C₁₂-polycycloalkenyl andC₅-C₁₂-spirocycloalkyl or R¹ and R³ or R² and R³ together denote asaturated or unsaturated C₃-C₄-alkyl bridge which may contain 1 to 2heteroatoms.

Preferably the substituent R₃ denotes C₁-C₆-alkyl or —C₃-C₁₂-cycloalkyl,particularly preferably methyl or cyclopentyl.

The substituent R⁴ may represent optionally substituted aryl orheteroaryl, preferably a group of general formula

The index n may represent 0, 1, 2, 3, 4 or 5, preferably 1 or 2,particularly preferably 1.

The substituent R⁵ may represent a group selected from among hydrogen,halogen, CHO, XH, —X—C₁-C₂-alkyl and an optionally substitutedC₁-C₃-alkyl group, preferably methyl.

Preferably the substituent R⁵ denotes methyl.

The substituent R⁶ may represent a group selected from among hydrogen,NH₂, XH, halogen and a C₁-C₃-alkyl group optionally substituted by oneor more halogen atoms.

Preferably the substituent R⁶ denotes hydrogen.

The substituent R⁷ may represent hydrogen, —CO—X—C₁-C₄-alkyl, preferably—CO—O-methyl or —CO—O-ethyl, —CO—NH—C₁-C₄-alkyl, preferably—CO—NH-methyl or —CO—NH-ethyl, or —CO—C₁-C₄-alkyl, preferably—CO-methyl. Preferably the substituent R⁷ denotes hydrogen.

X may in each case independently of one another denote oxygen orsulphur, preferably oxygen.

The substituent R⁸ may in each case independently of one another denotehydrogen or a group selected from among optionally substitutedC₁-C₄-alkyl, preferably methyl or ethyl, C₂-C₄-alkenyl, C₂-C₄-alkynyl,benzyl and phenyl. Preferably the substituent R⁸ denotes methyl, phenylor benzyl.

The substituent R⁹ which may be identical or different, may denote agroup selected from among optionally substituted C₁-C₆-alkyl, preferablymethyl, ethyl or isopropyl, C₂-C₆-alkenyl, preferably allyl orhomoallyl, C₂-C₆-alkynyl, preferably propargyl —O—C₁-C₆-alkyl,preferably —O-methyl or —O-ethyl, —O—C₂-C₆-alkenyl, —O—C₂-C₆-alkynyl,C₃-C₆-heterocycloalkyl, preferably piperazinyl, morpholinyl,pyrrolidinyl or piperidinyl, C₃-C₆-cycloalkyl, preferably cyclopropyl,cyclopentyl or cyclohexyl, aryl, preferably phenyl, or naphthalenyl,heteroaryl, preferably pyridinyl or pyrimidinyl, —O-aryl, preferably—O-phenyl, O-heteroaryl, preferably O-pyridinyl or O-pyrimidinyl,—O-cycloalkyl, preferably O-cyclopentyl, or O-cyclohexyl, and—O-heterocycloalkyl, preferably —O-morpholinyl, —O-piperidinyl,—O-pyrrolidinyl, or —O-piperazinyl, or

a group selected from among hydrogen, —CONH₂, —COOR⁸, —OCON(R⁸)₂,—N(R⁸)₂, —NHCOR⁸, —NHCON(R⁸)₂, —NO₂, CF₃, halogen, —O—C₁-C₆-alkyl-Q¹,—CONR⁸—C₁-C₁₀-alkyl-Q¹, —CONR⁸—C₂-C₁₀-alkenyl-Q¹, —CONR⁸-Q², halogen,OH, —SO₂R⁸, —SO₂N(R⁸)₂, —COR⁸, —COOR⁸, —N(R⁸)₂, —NHCOR⁸,—CONR⁸OC₁-C₁₀-alkyl-Q¹ and —CONR⁸O-Q².

Preferably the substituent R⁹ denotes —CONR⁸-Q² or—CONR⁸OC₁-C₁₀-alkyl-Q¹. The substituents R¹⁰ and R¹¹ may in each caseindependently of one another denote hydrogen or optionally substitutedC₁-C₄-alkyl, preferably hydrogen or methyl, or

R¹⁰ and R¹¹ may together denote a 2-5 membered alkyl bridge, preferablya 2-membered alkyl bridge.

Particularly preferably the substituents R¹⁰ and R¹¹ denote hydrogen.

Q¹ may represent hydrogen, —NHCOR⁸ or a group selected from among anoptionally substituted —NH-aryl, —NH-heteroaryl, aryl, preferablyphenyl, heteroaryl, C₃-C₈-cycloalkyl and heterocycloalkyl group.

Q² may represent hydrogen or a group selected from among an optionallysubstituted aryl, preferably phenyl, heteroaryl and C₃-C₈-cycloalkylgroup.

All the groups mentioned in the definitions of R¹ to R⁹ may optionallybe branched and/or substituted.

The compounds of general formula (I) may be prepared by the followingmethod of synthesis, while the substituents of general formulae (A1),(A2) and (I) are as hereinbefore defined. This method is to beunderstood as illustrating the invention without restricting it to theobject thereof.

A compound of formula (A1) is reacted with an optionally substitutedbenzylamine (A2) to obtain general formula (I). The compounds of formula(A1) may be obtained as described on page 23 of WO 2003/020722.Enantiomerically pure compounds (A1) with respect to the stereochemistryat R1/R2 may also be obtained analogously to the process describedtherein. The 4-aminomethyl-N-benzylbenzamide used may be obtained e.g.according to the following reference: H. G. Kazmirowski, P. Neuland, H.Landmann, F. Markwardt Pharmazie 1967, 22(9), 465-70.

The new compounds of general formula (I) may be prepared analogously tothe following Examples.

The following 2-chloro-dihydropteridinones were used in the syntheses:

EXAMPLE 9

0.5 g 1 was stirred together with 1.15 g 4-aminomethyl-N-benzylbenzamidein 2.5 mL sulpholane for 30 min to 160° C. After the reaction solutionhad cooled it was diluted with 20 mL methanol and the precipitate formedwas filtered off, washed again with methanol and dried. It yielded 470mg light brown crystals of m.p. 162° C.

EXAMPLE 10

0.2 g 1 was stirred with 0.4 g 4-aminomethylbenzenesulphonamide x HCland 0.34 mL 30% sodium methoxide solution in 1 mL sulpholane at 160° C.for 2 h. After cooling it was diluted with methanol and ether, filteredoff from the precipitate, the mother liquor was evaporated down and theresidue was extracted with methylene chloride and 2N hydrochloric acid.A yellow precipitate crystallised out from the methylene chloride phaseand this was filtered off and dried. It yielded 40 mg yellow crystals ofm.p. 248° C.

EXAMPLE 11

0.1 g 2 was melted together with 168 μL benzylamine without solvent at160° C. for 1 h and 45 minutes. After cooling the residue was dissolvedwith a little dichloromethane and methanol and combined with ether. Theprecipitate formed was filtered off and the mother liquor evaporateddown and subjected to chromatography on silica gel. The eluant used wasdichloromethane:methanol:aqueous ammonia solution in the ratio 95:5:0.5.Then the fractions containing the product were combined and evaporateddown. The residue was dissolved in ethyl acetate, combined with etherealHCl and petroleum ether and the precipitate was filtered off. It yielded0.08 g of a light brown hygroscopic solid.

EXAMPLE 12

0.1 g 2 and 95 μL 3-chlorobenzylamine were heated without solvent for 2h at 160° C. The cooled reaction mixture was digested with methanol anddichloromethane and combined with ether. The precipitate was filteredoff and the mother liquor was purified by chromatography as described inExample 11. The product fractions were combined and evaporated down.Then the product was dissolved in acetone, combined with an oxalic acidsolution in isopropanol and the precipitate was filtered off and dried.It yielded 72 mg of a white solid, m.p. 171° C.

EXAMPLE 14

0.1 g 2 and 100 μL 3-methoxybenzylamine were heated to 160° C. withoutsolvent for 2 h. The cooled reaction mixture was digested with methanoland dichloromethane and combined with ether. The precipitate wasfiltered off and the mother liquor was purified by chromatography asdescribed in Example 11. The product fractions were combined andevaporated down. Then the product was dissolved in acetone, combinedwith an oxalic acid solution in isopropanol and the precipitate wasfiltered off and dried. It yielded 97 mg of a white solid of m.p. 175°C.

The compounds of general formula (I) listed in Table 1, inter alia, wereobtained analogously to the method described above.

TABLE 1

Config. R⁹ R⁹ R⁹ Example **H/R2 R² R³ ortho meta para m.p. 1 H —CH₃ H HH 2 H —CH₃ H H Cl 250° C. 3 H —CH₃ H —CF₃ H 206° C. 4 H —CH₃ H —OCH₃ H194° C. 5 H —CH₃ H H —OCH₃ 195° C. 6 H —CH₃ H H F 253° C. 7 H —CH₃ —OCH₃H H 194° C. 8 H CH₃ H H —N(CH₃)₂ 235° C. 9 H —CH₃ H H

162° C. 10 H —CH₃ H H —SO₂NH₂ 248° C. 12 R —CH₂CH₃

H Cl H 171° C. 13 R —CH₂CH₃

H H Cl 149° C. 14 R —CH₂CH₃

—OCH₃ H H 175° C. 15 R —CH₂CH₃

H H H 144° C. 16 R —CH₂CH₃

Cl H H 177° C. 17 R —CH₂CH₃

H H —OCH₃ *position of bond

As has been found, the compounds of general formula (I) arecharacterised by their wide range of applications in the therapeuticfield. Particular mention should be made of those applications in whichthe inhibition of specific cell cycle kinases, particularly theinhibiting effect on the proliferation of cultivated human tumour cellsbut also the proliferation of other cells, such as endothelial cells,for example, plays a part.

As could be demonstrated by DNA staining followed by FACS analysis, theinhibition of proliferation brought about by the compounds according tothe invention is mediated by the arrest of the cells, particularly atthe G2/M phase of the cell cycle. The cells arrest, depending on thecells used, for a specific length of time in this phase of the cellcycle before programmed cell death is initiated. An arrest in the G2/Mphase of the cell cycle is triggered, for example, by the inhibition ofspecific cell cycle kinases. In view of their biological properties thecompounds of general formula I according to the invention, their isomersand their physiologically acceptable salts are suitable for thetreatment of diseases characterised by excessive or abnormal cellproliferation.

Such diseases include, for example: viral infections (e.g. HIV andKaposi's sarcoma); inflammatory and autoimmune diseases (e.g. colitis,arthritis, Alzheimer's disease, glomerulonephritis and wound healing);bacterial, fungal and/or parasitic infections; leukaemias, lymphoma andsolid tumours; skin diseases (e.g. psoriasis); bone diseases;cardiovascular diseases (e.g. restenosis and hypertrophy). They are alsosuitable for protecting proliferating cells (e.g. hair, intestinal,blood and progenitor cells) from damage to their DNA caused byradiation, UV treatment and/or cytostatic treatment (Davis et al.,2001).

The new compounds may be used for the prevention, short-term orlong-term treatment of the abovementioned diseases, also in combinationwith other active substances used for the same indications, e.g.cytostatics, hormones or antibodies.

The activity of the compounds according to the invention was determinedin the PLK1 inhibition assay, in the cytotoxicity test on cultivatedhuman tumour cells and/or in a FACS analysis, for example on HeLaS3cells. In both test methods, the compounds exhibited a good to very goodactivity, i.e. for example an EC₅₀ value in the HeLaS3 cytotoxicity testof less than 5 μmol/L, generally less than 1 μmol/L and an IC₅₀ value inthe PLK1 inhibition assay of less than 1 μmol/L.

PLK1 Kinase Assay

Preparation of Enzyme:

Recombinant human PLK1 enzyme attached to GST at its N-terminal end isisolated from Baculovirus-infected insect cells (Sf21). Purification iscarried out by affinity chromatography on glutathione sepharose columns.

4×10⁷ Sf21 cells (Spodoptera frugiperda) in 200 ml of Sf-900 II Serumfree insect cell medium (Life Technologies) are seeded in a spinnerflask. After 72 hours' incubation at 27° C. and 70 rpm, 1×10⁸ Sf21 cellsare seeded in a total of 180 ml medium in a new spinner flask. Afteranother 24 hours, 20 ml of recombinant Baculovirus stock suspension areadded and the cells are cultivated for 72 hours at 27° C. at 70 rpm. 3hours before harvesting, okadaic acid is added (Calbiochem, finalconcentration 0.1 μM) and the suspension is incubated further. The cellnumber is determined, the cells are removed by centrifuging (5 minutes,4° C., 800 rpm) and washed 1× with PBS (8 g NaCl/I, 0.2 g KCl/I, 1.44 gNa₂HPO₄/I, 0.24 g KH₂PO₄/I). After centrifuging again the pellet isflash-frozen in liquid nitrogen. Then the pellet is quickly thawed andresuspended in ice-cold lysing buffer (50 mM HEPES pH 7.5, 10 mM MgCl₂,1 mM DTT, 5 μg/ml leupeptin, 5 μg/ml aprotinin, 100 μM NaF, 100 μM PMSF,10 mM β-glycerolphosphate, 0.1 mM Na₃VO₄, 30 mM 4-nitrophenylphosphate)to give 1×10⁸ cells/17.5 ml. The cells are lysed for 30 minutes on ice.After removal of the cell debris by centrifugation (4000 rpm, 5 minutes)the clear supernatant is combined with glutathione sepharose beads (1 mlresuspended and washed beads per 50 ml of supernatant) and the mixtureis incubated for 30 minutes at 4° C. on a rotating board. Then the beadsare washed with lysing buffer and the recombinant protein is eluted fromthe beads with 1 ml eluting buffer/ml resuspended beads (eluting buffer:100 mM Tris/HCl pH=8.0, 120 mM NaCl, 20 mM reduced glutathione (SigmaG-4251), 10 mM MgCl₂, 1 mM DTT). The protein concentration is determinedby Bradford Assay.

Assay

The following components are combined in a well of a 96-wellround-bottomed dish (Greiner bio-one, PS Microtitre plate No. 650101):

-   -   10 μl of the compound to be tested in variable concentrations        (e.g. beginning at 300 μM, and dilution to 1:3) in 6% DMSO, 0.5        mg/ml casein (Sigma C-5890), 60 mM β-glycerophosphate, 25 mM        MOPS pH=7.0, 5 mM EGTA, 15 mM MgCl₂, 1 mM DTT    -   20 μl substrate solution (25 mM MOPS pH=7.0, 15 mM MgCl₂, 1 mM        DTT, 2.5 mM EGTA, 30 mM β-glycerophosphate, 0.25 mg/ml casein)    -   20 μl enzyme dilution (1:100 dilution of the enzyme stock in 25        mM MOPS pH=7.0, 15 mM MgCl₂, 1 mM DTT)    -   10 μl ATP solution (45 μM ATP with 1.11×10⁶ Bq/ml        gamma-P33-ATP).

The reaction is started by adding the ATP solution and continued for 45minutes at 30° C. with gentle shaking (650 rpm on an IKA SchuttlerMTS2). The reaction is stopped by the addition of 125 μl of ice-cold 5%TCA per well and incubated on ice for at least 30 minutes. Theprecipitate is transferred by harvesting onto filter plates (96-wellmicrotitre filter plate: UniFilter-96, GF/B; Packard; No. 6005177), thenwashed four times with 1% TCA and dried at 60° C. After the addition of35 μl scintillation solution (Ready-Safe; Beckmann) per well the plateis sealed shut with sealing tape and the amount of P33 precipitated ismeasured with the Wallac Betacounter.

The measured data are evaluated using the standard Graphpad software(Levenburg-Marquard Algorhythmus).

Measurement of Cytotoxicity on Cultivated Human Tumour Cells

To measure cytotoxicity on cultivated human tumour cells, cells ofcervical carcinoma tumour cell line HeLa S3 (obtained from American TypeCulture Collection (ATCC)) are cultivated in Ham's F12 Medium (LifeTechnologies) and 10% foetal calf serum (Life Technologies) andharvested in the log growth phase. Then the HeLa S3 cells are placed in96-well plates (Costar) at a density of 1000 cells per well andincubated overnight in an incubator (at 37° C. and 5% CO2), while oneach plate 6 wells are filled with medium alone (3 wells as the mediumcontrol, 3 wells for incubation with reduced AlamarBlue reagent). Theactive substances are added to the cells in various concentrations(dissolved in DMSO; DMSO final concentration: 0.1%) (in each case as atriple measurement). After 72 hours incubation 20 μl AlamarBlue reagent(AccuMed International) are added to each well, and the cells areincubated for a further 7 hours. As a control, 20 μl reduced AlamarBluereagent is added to each of 3 wells (AlamarBlue reagent, which isautoclaved for 30 min). After 7 h incubation the colour change of theAlamarBlue reagent in the individual wells is determined in a PerkinElmer fluorescence spectrophotometer (excitation 530 nm, emission 590nm, slits 15, integrate time 0.1). The amount of AlamarBlue reagentreacted represents the metabolic activity of the cells. The relativecell activity is calculated as a percentage of the control (HeLa S3cells without inhibitor) and the active substance concentration whichinhibits the cell activity by 50% (IC₅₀) is derived. The values arecalculated from the average of three individual measurements—withcorrection of the dummy value (medium control).

FACS Analysis

Propidium iodide (PI) binds stoichiometrically to double-stranded DNA,and is thus suitable for determining the proportion of cells in the G1,S, and G2/M phase of the cell cycle on the basis of the cellular DNAcontent. Cells in the G0 and G1 phase have a diploid DNA content (2N),whereas cells in the G2 or mitosis phase have a 4N DNA content.

For PI staining, for example, 0.4 million HeLa S3 cells were seeded ontoa 75 cm² cell culture flask, and after 24 h either 0.1% DMSO was addedas control or the substance was added in various concentrations (in 0.1%DMSO). The cells were incubated for 24 h with the substance or with DMSObefore the cells were washed 2× with PBS and then detached withtrypsin/EDTA. The cells were centrifuged (1000 rpm, 5 min, 4° C.), andthe cell pellet was washed 2× with PBS before the cells were resuspendedin 0.1 ml PBS. Then the cells were fixed with 80% ethanol for 16 hoursat 4° C. or alternatively for 2 hours at −20° C. The fixed cells werecentrifuged (1000 rpm, 5 min, 4° C.), washed with PBS and thencentrifuged again. The cell pellet was resuspended in 2 ml 0.25% TritonX-100 in PBS, and incubated on ice for 5 min before 5 ml PBS are addedand the mixture is centrifuged again. The cell pellet was resuspended in350 μl PI staining solution (0.1 mg/ml RNase A (Sigma, No. R-4875), 10μg/ml prodium iodide (Sigma, No. P-4864) in 1×PBS). The cells wereincubated for 20 min in the dark with the staining buffer before beingtransferred into sample measuring containers for the FACS scan. The DNAmeasurement was carried out in a Becton Dickinson FACS Analyzer, with anargon laser (500 mW, emission 488 nm), and the DNA Cell Quest Programme(BD). The logarithmic PI fluorescence was determined with a band-passfilter (BP 585/42). The cell populations in the individual cell cyclephases were quantified using the ModFit LT Programme made by BectonDickinson.

The compounds according to the invention were also tested accordingly onother tumour cells. For example, these compounds are effective oncarcinomas of all kinds of tissue (e.g. breast (MCF7); colon (HCT116),head and neck (FaDu), lung (NCI-H460), pancreas (BxPC-3), prostate(DU145)), sarcomas (e.g. SK-UT-1B, Saos-2), leukaemias and lymphomas(e.g. HL-60, Jurkat, THP-1) and other tumours (e.g. melanomas (BRO),gliomas (U-87MG)) and could be used for such indications. This isevidence of the broad applicability of the compounds according to theinvention for the treatment of all kinds of tumour types.

The compounds of general formula (I) may be used on their own or inconjunction with other active substances according to the invention,optionally also in conjunction with other pharmacologically activesubstances. Suitable preparations include for example tablets, capsules,suppositories, solutions, —particularly solutions for injection (s.c.,i.v., i.m.) and infusion—elixirs, emulsions or dispersible powders. Thecontent of the pharmaceutically active compound(s) should be in therange from 0.1 to 90 wt.-%, preferably 0.5 to 50 wt.-% of thecomposition as a whole, i.e. in amounts which are sufficient to achievethe dosage range specified below. The doses specified may, if necessary,be given several times a day.

Suitable tablets may be obtained, for example, by mixing the activesubstance(s) with known excipients, for example inert diluents such ascalcium carbonate, calcium phosphate or lactose, disintegrants such ascorn starch or alginic acid, binders such as starch or gelatine,lubricants such as magnesium stearate or talc and/or agents for delayingrelease, such as carboxymethyl cellulose, cellulose acetate phthalate,or polyvinyl acetate. The tablets may also comprise several layers.

Coated tablets may be prepared accordingly by coating cores producedanalogously to the tablets with substances normally used for tabletcoatings, for example collidone or shellac, gum arabic, talc, titaniumdioxide or sugar. To achieve delayed release or preventincompatibilities the core may also consist of a number of layers.Similarly the tablet coating may consist of a number or layers toachieve delayed release, possibly using the excipients mentioned abovefor the tablets.

Syrups or elixirs containing the active substances or combinationsthereof according to the invention may additionally contain a sweetenersuch as saccharine, cyclamate, glycerol or sugar and a flavour enhancer,e.g. a flavouring such as vanillin or orange extract. They may alsocontain suspension adjuvants or thickeners such as sodium carboxymethylcellulose, wetting agents such as, for example, condensation products offatty alcohols with ethylene oxide, or preservatives such asp-hydroxybenzoates.

Solutions for injection and infusion are prepared in the usual way, e.g.with the addition of isotonic agents, preservatives such asp-hydroxybenzoates, or stabilisers such as alkali metal salts ofethylenediamine tetraacetic acid, optionally using emulsifiers and/ordispersants, whilst if water is used as the diluent, for example,organic solvents may optionally be used as solvating agents ordissolving aids, and transferred into injection vials or ampoules orinfusion bottles.

Capsules containing one or more active substances or combinations ofactive substances may for example be prepared by mixing the activesubstances with inert carriers such as lactose or sorbitol and packingthem into gelatine capsules.

Suitable suppositories may be made for example by mixing with carriersprovided for this purpose, such as neutral fats or polyethyleneglycol orthe derivatives thereof.

Excipients which may be used include, for example, water,pharmaceutically acceptable organic solvents such as paraffins (e.g.petroleum fractions), vegetable oils (e.g. groundnut or sesame oil),mono- or polyfunctional alcohols (e.g. ethanol or glycerol), carrierssuch as e.g. natural mineral powders (e.g. kaolins, clays, talc, chalk),synthetic mineral powders (e.g. highly dispersed silicic acid andsilicates), sugars (e.g. cane sugar, lactose and glucose) emulsifiers(e.g. lignin, spent sulphite liquors, methylcellulose, starch andpolyvinylpyrrolidone) and lubricants (e.g. magnesium stearate, talc,stearic acid and sodium lauryl sulphate).

The preparations are administered by the usual methods, preferably byoral or transdermal route, most preferably by oral route. For oraladministration the tablets may, of course contain, apart from theabovementioned carriers, additives such as sodium citrate, calciumcarbonate and dicalcium phosphate together with various additives suchas starch, preferably potato starch, gelatine and the like. Moreover,lubricants such as magnesium stearate, sodium lauryl sulphate and talcmay be used at the same time for the tabletting process. In the case ofaqueous suspensions the active substances may be combined with variousflavour enhancers or colourings in addition to the excipients mentionedabove.

For parenteral use, solutions of the active substances with suitableliquid carriers may be used.

The dosage for intravenous use is from 1-1000 mg per hour, preferablybetween 5 and 500 mg per hour.

However, it may sometimes be necessary to depart from the amountsspecified, depending on the body weight, the route of administration,the individual response to the drug, the nature of its formulation andthe time or interval over which the drug is administered. Thus, in somecases it may be sufficient to use less than the minimum dose givenabove, whereas in other cases the upper limit may have to be exceeded.When administering large amounts it may be advisable to divide them upinto a number of smaller doses spread over the day.

The formulation examples which follow illustrate the present inventionwithout restricting its scope:

Examples of Pharmaceutical Formulations

A) Tablets per tablet active substance 100 mg lactose 140 mg corn starch240 mg polyvinylpyrrolidone 15 mg magnesium stearate 5 mg 500 mg

The finely ground active substance, lactose and some of the corn starchare mixed together. The mixture is screened, then moistened with asolution of polyvinylpyrrolidone in water, kneaded, wet-granulated anddried. The granules, the remaining corn starch and the magnesiumstearate are screened and mixed together. The mixture is compressed toproduce tablets of suitable shape and size.

B) Tablets per tablet active substance 80 mg lactose 55 mg corn starch190 mg microcrystalline cellulose 35 mg polyvinylpyrrolidone 15 mgsodium-carboxymethyl starch 23 mg magnesium stearate 2 mg 400 mg

The finely ground active substance, some of the corn starch, lactose,microcrystalline cellulose and polyvinylpyrrolidone are mixed together,the mixture is screened and worked with the remaining corn starch andwater to form a granulate which is dried and screened. Thesodiumcarboxymethyl starch and the magnesium stearate are added andmixed in and the mixture is compressed to form tablets of a suitablesize.

C) Ampoule solution active substance 50 mg sodium chloride 50 mg waterfor inj. 5 ml

The active substance is dissolved in water at its own pH or optionallyat pH 5.5 to 6.5 and sodium chloride is added to make it isotonic. Thesolution obtained is filtered free from pyrogens and the filtrate istransferred under aseptic conditions into ampoules which are thensterilised and sealed by fusion. The ampoules contain 5 mg, 25 mg and 50mg of active substance.

1. A compound of formula (I),

wherein R¹, R² which may be identical or different, denote a groupselected from among optionally substituted C₁-C₁₀-alkyl,C₃-C₈-cycloalkyl and hydrogen, or R¹ and R² together denote a 2- to5-membered alkyl bridge, R³ denotes hydrogen or a group selected fromamong optionally substituted C₁-C₁₂-alkyl and C₃-C₁₂-cycloalkyl, or R¹and R³ or R² and R³ together denote a saturated or unsaturatedC₃-C₄-alkyl bridge which may contain 1 to 2 heteroatoms, R⁴ denotesoptionally mono-substituted aryl or, R⁵ denotes a group selected fromamong hydrogen, CHO, XH, —X—C₁-C₂-alkyl and an optionally substitutedC₁-C₃-alkyl group, R⁶ denotes a group selected from among hydrogen, NH₂,XH, halogen and a C₁-C₃-alkyl group optionally substituted by one ormore halogen atoms, R⁷ denotes hydrogen or —CO—C₁-C₄-alkyl,—CO—NH—C₁-C₄-alkyl, —CO—X—C₁-C₄-alkyl, and X in each case independentlyof one another denote O or S, R⁸ in each case independently of oneanother denote hydrogen or a group selected from among optionallysubstituted C₁-C₄-alkyl, C₂-C₄-alkenyl, C₂-C₄-alkynyl, benzyl andphenyl, R¹⁰ and R¹¹ in each case independently of one another denotehydrogen or a group selected from among optionally substitutedC₁-C₄-alkyl, or R¹⁰ and R¹¹ together denote a 2-5 membered alkyl bridge,or the pharmacologically acceptable acid addition salt thereof.
 2. Thecompound according to claim 1, wherein R¹ to R⁴ have the meaningsspecified, R⁵ denotes methyl, and R⁶ and R⁷ denote hydrogen, R¹⁰ and R¹¹in each case independently of one another denote hydrogen or methyl, orR¹⁰ and R¹¹ together denote cyclopropyl.
 3. The compound according toclaim 2, wherein R³ to R⁷, R¹⁰ and R¹¹ have the meanings specified andR¹, R² which may be identical or different, denote hydrogen or a groupselected from optionally substituted C₁-C₆-alkyl, or R¹ and R² togetherdenote a 2- to 5-membered alkyl bridge.
 4. The compound according toclaim 1, wherein R³ is hydrogen or contains a group selected from amongoptionally substituted C₁-C₁₂-alkyl and C₃-C₁₂-cycloalkyl.
 5. Thecompound according to claim 4, wherein R¹ to R³, R⁵ to R⁷, R¹⁰ and R¹¹have the meanings specified, and R⁴ denotes a group of formula

R⁹ which may be identical or different, denotes a group selected fromamong optionally substituted C₁-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl,—O—C₁-C₆-alkyl, —O—C₂-C₆-alkenyl, —O—C₂-C₆-alkynyl,C₃-C₆-heterocycloalkyl, C₃-C₆-cycloalkyl, aryl, heteroaryl, —O-aryl,—O-heteroaryl, —O-cycloalkyl, and —O-heterocycloalkyl or a groupselected from among hydrogen, —CONH₂, —COOR⁸, —OCON(R⁸)₂, —N(R⁸)₂,—NHCOR⁸, —NHCON(R⁸)₂, —NO₂, CF₃, halogen, —O—C₁-C₆-alkyl-Q¹,—CONR⁸—C₁-C₁₀-alkyl-Q¹, —CONR⁸—C₂-C₁₀-alkenyl-Q¹, —CONR⁸—Q², halogen,OH, —SO₂R⁸, —SO₂N(R⁸)₂, —COR⁸, —COOR⁸, —N(R⁸)₂, —NHCOR⁸,—CONR⁸OC₁-C₁₀-alkyl-Q¹ and CONR⁸O—Q², R⁸ in each case independently ofone another denote hydrogen or a group selected from among optionallysubstituted C₁-C₄-alkyl, C₂-C₄-alkenyl, C₂-C₄-alkynyl and phenyl, Q¹denotes hydrogen, —NHCOR⁸, or a group selected from among an optionallysubstituted —NH-aryl, —NH-heteroaryl, aryl, heteroaryl, C₃-C₈-cycloalkyland heterocycloalkyl group, Q² denotes hydrogen or a group selected fromamong an optionally substituted aryl, heteroaryl and C₃-C₈-cycloalkylgroup, and n denotes 0,
 1. 6. The compound according to claim 5, whereinQ¹, Q², n, R⁴ to R⁸ have the meanings specified, R¹, R² which may beidentical or different, denote hydrogen or a group selected from amongmethyl, ethyl, and propyl or R¹ and R² together represent cyclopropyl,R³ denotes hydrogen, or denotes optionally substituted C₁-C₆-alkyl oroptionally substituted and/or bridged C₃-C₁₂-cycloalkyl, and R¹⁰ and R¹¹denote hydrogen.
 7. The compound according to claim 5, wherein Q¹, Q²,n, R¹ to R⁴, R⁶ to R⁸, R¹⁰ and R¹¹ have the meanings specified, and R⁹which may be identical or different, denote hydrogen or a group selectedfrom among halogen, (C₁-C₄-alkyl)₂N—, CF₃, NH₂SO₂—, —CONH—C₆-C₁₄-aryl,—CONH—C₁-C₄-alkyl-C₆-C₁₄-aryl and —O—C₁-C₄-alkyl.
 8. A pharmaceuticalpreparation comprising as active substance one or more compounds offormula (I) according to claim 1 combined with one or more conventionalexcipients or carriers or both.